Dysregulation of
receptor tyrosine kinases (RTKs) contributes to several aspects of
oncogenesis including drug resistance. In
melanoma, distinct RTKs have been involved in BRAF inhibitors (BRAFi) resistance, yet the utility of RTKs expression pattern to identify intrinsically resistant
tumors has not been assessed. Transcriptional profiling of RTKs and integration with a previous classification, reveals three robust subtypes in two independent datasets of
melanoma cell lines and one cohort of
melanoma samples. This classification was validated by Western blot in a panel of patient-derived
melanoma cell lines. One of the subtypes identified here for the first time displayed the highest and lowest expression of EGFR and ERBB3, respectively, and included BRAF-mutant
tumors all intrinsically resistant to BRAFi
PLX4720, as assessed by analysis of the
Cancer Cell Line Encyclopedia pharmacogenomic study and by in vitro growth inhibition assays. High levels of EGFR were detected, even before
therapy, in
tumor cells of one of three
melanoma patients unresponsive to BRAFi. Use of different pharmacological inhibitors highlighted the relevance of PI3K/mTOR signaling for growth of this PLX4720-resistant subtype. Our results identify a specific molecular profile of
melanomas intrinsically resistant to BRAFi and suggest the PI3K/mTOR pathway as a potential therapeutic target for these
tumors.